The goal of this application is to determine whether sorafenib may be effective at treating hepatopulmonary syndrome (HPS). Cirrhotic liver disease afflicts nearly 3 million Americans, and complications of cirrhosis are the fourth leading cause of death between ages 45-65. HPS is one such complication which results when pulmonary microvascular dilations lead to an increased alveolar-arterial oxygen gradient (AaPO2) and intrapulmonary transit of bubbles visualized by echocardiography after injection of agitated saline. HPS occurs in 33% of patients evaluated for liver transplantation amounting to hundreds of thousands Americans with HPS. We have shown that HPS worsens quality of life and doubles the already-significantly elevated risk of death of the cirrhotic patient. Unfortunately, te significant public health implications of HPS are magnified by the lack of any medical therapies for this lung disease. The two principal investigators (PIs) of the current application have demonstrated the importance of angiogenesis in HPS in humans and in animal models. Recently, our team has shown that the tyrosine kinase-inhibitor sorafenib prevents aberrant angiogenesis in the lungs, reverses gas exchange abnormalities, and reduces intrapulmonary shunting in the HPS animal model. Sorafenib has been studied extensively in patients with cirrhosis with hepatocellular carcinoma and is FDA-approved in this population. We propose a randomized, double-blind, placebo-controlled parallel trial of 50 patients to determine whether sorafenib affects AaPO2 at three months in patients with HPS. We hypothesize that sorafenib will decrease the AaPO2 compared to placebo. We will also determine the effect of sorafenib on intrapulmonary shunting and biomarkers of angiogenesis, including circulating hematopoietic progenitor cells and other plasma biomarkers. Finally, we will assess the impact of sorafenib on the six-minute walk distance and health-related quality of life of patients with HPS. We will determine the safety and potential efficacy of sorafenib as a novel therapeutic for the treatment of HPS.